PT  - JOURNAL ARTICLE
AU  - Kaczanowska, Sabina
AU  - Joseph, Ann Mary
AU  - Guo, Jitao
AU  - Tsai, Alexander K
AU  - Lasola, Jackline Joy
AU  - Younger, Kenisha
AU  - Zhang, Yuji
AU  - Gonzales, Cruz Velasco
AU  - Davila, Eduardo
TI  - A Synthetic CD8α:MyD88 Coreceptor Enhances CD8<sup>+</sup> T-cell Responses to Weakly Immunogenic and Lowly Expressed Tumor Antigens
AID  - 10.1158/0008-5472.CAN-17-0653
DP  - 2017 Dec 15
TA  - Cancer Research
PG  - 7049--7058
VI  - 77
IP  - 24
4099  - http://cancerres.aacrjournals.org/content/77/24/7049.short
4100  - http://cancerres.aacrjournals.org/content/77/24/7049.full
SO  - Cancer Res2017 Dec 15; 77
AB  - T cell–based immunotherapies are a promising approach for patients with advanced cancers. However, various obstacles limit T-cell efficacy, including suboptimal T-cell receptor (TCR) activation and an immunosuppressive tumor environment. Here, we developed a fusion protein by linking CD8α and MyD88 (CD8α:MyD88) to enhance CD8+ T-cell responses to weakly immunogenic and poorly expressed tumor antigens. CD8α:MyD88–engineered T cells exhibited increased proliferation and expression of effector and costimulatory molecules in a tumor antigen–dependent manner. These effects were accompanied by elevated activation of TCR and Toll-like receptor signaling-related proteins. CD8α:MyD88–expressing T cells improved antitumor responses in mice. Enhanced antitumor activity was associated with a unique tumor cytokine/chemokine signature, improved T-cell infiltration, reduced markers of T-cell exhaustion, elevated levels of proteins associated with antigen presentation, and fewer macrophages with an immunosuppressive phenotype in tumors. Given these observations, CD8α:MyD88 represents a unique and versatile approach to help overcome immunosuppression and enhance T-cell responses to tumor antigens. Cancer Res; 77(24); 7049–58. ©2017 AACR.